Neurostimulation titration utilizing t-wave alternans

ABSTRACT

Systems and methods are provided for delivering neurostimulation therapies to patients. A titration process is used to gradually increase the stimulation intensity to a desired therapeutic level until a target T-wave alternans change from a baseline T-wave alternans is achieved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/938,641 filed Nov. 11, 2015, which claims priority to U.S.Provisional Application No. 62/078,600, filed on Nov. 12, 2014, both ofwhich are incorporated herein by reference in their entirety.

FIELD

This application relates to neuromodulation and, more specifically, toimproved systems and methods for titrating stimulation therapies.

BACKGROUND

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF. Forinstance, VNS has been demonstrated in canine studies as efficacious insimulated treatment of AF and heart failure, such as described in Zhanget al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control andAttenuates Systemic Inflammation and Heart Failure Progression in aCanine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699(Sep. 22, 2009), the disclosure of which is incorporated by reference.The results of a multi-center open-label phase II study in which chronicVNS was utilized for CHF patients with severe systolic dysfunction isdescribed in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A Newand Promising Therapeutic Approach for Chronic Heart Failure,” EuropeanHeart Journal, 32, pp. 847-855 (Oct. 28, 2010).

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's tolerancethreshold, or tolerance zone boundary, gradually increases, allowing foran increase in intensity during subsequent titration sessions. Thetitration process can take significantly longer in practice because theincrease in intensity is generally performed by a physician or otherhealthcare provider, and thus, for every step in the titration processto take place, the patient has to visit the provider's office to havethe titration performed. Scheduling conflicts in the provider's officemay increase the time between titration sessions, thereby extending theoverall titration process, during which the patient in need of VNS doesnot receive the VNS at the full therapeutic intensity.

For patients receiving VNS therapy for the treatment of epilepsy, atitration process that continues over an extended period of time, suchas six to twelve months, may be somewhat acceptable because thepatient's health condition typically would not worsen in that period oftime. However, for patients being treated for other health conditions,such as CHF, the patient's condition may degrade rapidly if leftuntreated. As a result, there is a much greater urgency to completingthe VNS titration process when treating a patient with a time-sensitivecondition, such as CHF.

Accordingly, a need remains for an approach to efficiently titrateneurostimulation therapy for treating chronic cardiac dysfunction andother conditions.

SUMMARY

Systems and methods are provided for delivering neurostimulationtherapies to patients. A titration process is used to gradually increasethe stimulation intensity to a desired therapeutic level until a targetT-wave alternans change from a baseline T-wave alternans is achieved.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 5.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIGS. 8A-8C are illustrative charts reflecting a heart rate response togradually increased stimulation intensity at different frequencies.

FIG. 9 illustrates a method for delivering vagus nerve stimulationtherapy.

FIG. 10 illustrates a titration process in accordance with embodimentsof the present invention.

FIGS. 11A-11B are block diagrams of neurostimulation systems inaccordance with embodiments of the present invention.

FIG. 12 illustrates a titration process with variable titrationparameters in accordance with embodiments of the present invention.

FIG. 13 is a scatter plot illustrating stimulation output current andcorresponding T-wave alternans changes from baseline.

FIGS. 14A-14B are illustrations of a method of assessing T-wavealternans in accordance with embodiments of the present invention.

FIGS. 15A-15B are plots illustrating heart rate turbulence response forpatients receiving VNS therapy in accordance with embodiments of thepresent invention.

FIG. 16 is a bar chart illustrating T-wave alternan magnitude levels forpatients receiving different stimulation levels in accordance withembodiments of the present invention.

FIG. 17 is a bar chart illustrating heart rate turbulence slope levelsfor patients receiving different stimulation levels in accordance withembodiments of the present invention.

DETAILED DESCRIPTION

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, in accordance with embodiments of thepresent invention. The VNS provided through the stimulation system 11operates under several mechanisms of action. These mechanisms includeincreasing parasympathetic outflow and inhibiting sympathetic effects byinhibiting norepinephrine release and adrenergic receptor activation.More importantly, VNS triggers the release of the endogenousneurotransmitter acetylcholine and other peptidergic substances into thesynaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and anti-inflammatory effects as well as beneficialeffects at the level of the central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The stimulating nerve electrode assembly 125, preferablycomprising at least an electrode pair, is conductively connected to thedistal end of an insulated, electrically conductive lead assembly 13 andelectrodes 14. The electrodes 14 may be provided in a variety of forms,such as, e.g., helical electrodes, probe electrodes, cuff electrodes, aswell as other types of electrodes.

The implantable vagus stimulation system 11 can be remotely accessedfollowing implant through an external programmer, such as the programmer40 shown in FIG. 3 and described in further detail below. The programmer40 can be used by healthcare professionals to check and program theneurostimulator 12 after implantation in the patient 10 and to adjuststimulation parameters during the initial stimulation titration process.In some embodiments, an external magnet may provide basic controls, suchas described in commonly assigned U.S. Pat. No. 8,600,505, entitled“Implantable Device For Facilitating Control Of Electrical StimulationOf Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,”the disclosure of which is incorporated by reference. For furtherexample, an electromagnetic controller may enable the patient 10 orhealthcare professional to interact with the implanted neurostimulator12 to exercise increased control over therapy delivery and suspension,such as described in commonly-assigned U.S. Pat. No. 8,571,654, entitled“Vagus Nerve Neurostimulator With Multiple Patient-Selectable Modes ForTreating Chronic Cardiac Dysfunction,” the disclosure of which isincorporated by reference. For further example, an external programmermay communicate with the neurostimulation system 11 via other wired orwireless communication methods, such as, e.g., wireless RF transmission.Together, the implantable vagus stimulation system 11 and one or more ofthe external components form a VNS therapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. A study of the relationship between cardiac autonomic nerveactivity and blood pressure changes in ambulatory dogs is described inJ. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure inAmbulatory Dogs,” Heart Rhythm, Vol. 11(2), pp. 307-313 (February 2014).Generally, cervical vagus nerve stimulation results in propagation ofaction potentials from the site of stimulation in a bi-directionalmanner. The application of bi-directional propagation in both afferentand efferent directions of action potentials within neuronal fiberscomprising the cervical vagus nerve improves cardiac autonomic balance.Afferent action potentials propagate toward the parasympathetic nervoussystem's origin in the medulla in the nucleus ambiguus, nucleus tractussolitarius, and the dorsal motor nucleus, as well as towards thesympathetic nervous system's origin in the intermediolateral cell columnof the spinal cord. Efferent action potentials propagate toward theheart 17 to activate the components of the heart's intrinsic nervoussystem. Either the left or right vagus nerve 15, 16 can be stimulated bythe stimulation system 11. The right vagus nerve 16 has a moderatelylower (approximately 30%) stimulation threshold than the left vagusnerve 15 for heart rate effects at the same stimulation frequency andpulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS THERAPY DEMIPULSE Model 103or ASPIRESR Model 106 pulse generator, manufactured and sold byLivallova PLC, Houston, Tex., although other manufactures and types ofimplantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PERENNIADURAModel 303 lead, or PERENNIAFLEX Model 304 lead, also manufactured andsold by Livallova PLC, in three sizes based, for example, on a helicalelectrode inner diameter, although other manufactures and types ofsingle-pin receptacle-compatible therapy leads and electrodes could alsobe used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, within which thestimulation parameters and timing cycles can be stored. Other electroniccircuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown), asetscrew, and a spring contact (not shown) that electrically connects tothe lead ring, thus completing the electrical circuit 26.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an electrocardiogram(ECG)-type electrode. Through the electrode, the patient's heart beatcan be sensed by detecting ventricular depolarization. In a furtherembodiment, a plurality of electrodes can be used to sense voltagedifferentials between electrode pairs, which can undergo signalprocessing for cardiac physiological measures, for instance, detectionof the P-wave, QRS complex, and T-wave. The heart rate sensor 31provides the sensed heart rate to the control and logic circuitry assensory inputs that can be used to determine the onset or presence ofarrhythmias, particularly VT, and/or to monitor and record changes inthe patient's heart rate over time or in response to applied stimulationsignals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28 and metal connector ring. During implantation,the connector pin 28 is guided through the receptacle 25 into the header24 and securely fastened in place using a setscrew (not shown) thatengages the connector pin 28 to electrically couple one electrode of thelead assembly 13 to the neurostimulator 12 while the spring contactmakes electrical contact to the ring connected to the other electrode.On a distal end, the lead assembly 13 terminates with the electrode 14,which bifurcates into a pair of anodic and cathodic electrodes 62 (asfurther described infra with reference to FIG. 4). In one embodiment,the lead connector 27 is manufactured using silicone and the connectorpin 28 and ring are made of stainless steel, although other suitablematerials could be used, as well. The insulated lead body 13 utilizes asilicone-insulated alloy conductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a proximal anode anda distal cathode, or a proximal cathode and a distal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters, suchas described in commonly-assigned U.S. Pat. Nos. 8,600,505 and8,571,654, cited supra. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byLivallova PLC, and the application software 45 can be adapted from theModel 250 Programming Software suite, licensed by Livallova PLC. Otherconfigurations and combinations of external programmer 40, programmingwand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. In other embodiments, the programming computer maycommunicate with the implanted neurostimulator 12 using other wirelesscommunication methods, such as wireless RF transmission. The programmingcomputer 41 may further be configured to receive inputs, such asphysiological signals received from patient sensors (e.g., implanted orexternal). These sensors may be configured to monitor one or morephysiological signals, e.g., vital signs, such as body temperature,pulse rate, respiration rate, blood pressure, etc. These sensors may becoupled directly to the programming computer 41 or may be coupled toanother instrument or computing device which receives the sensor inputand transmits the input to the programming computer 41. The programmingcomputer 41 may monitor, record, and/or respond to the physiologicalsignals in order to effectuate stimulation delivery in accordance withembodiments of the present invention.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

FIG. 4 is a diagram showing the helical electrodes 14 provided on thestimulation lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16in situ 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a proximal anode and a distalcathode, or a proximal cathode and a distal anode. In addition, ananchor tether 53 is fastened over the lead bodies 57, 58 that maintainsthe helical electrodes' position on the vagus nerve 61 followingimplant. In one embodiment, the conductors of the electrodes 51, 52 aremanufactured using a platinum and iridium alloy, while the helicalmaterials of the electrodes 51, 52 and the anchor tether 53 are asilicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Pat. No. 8,630,709, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” the disclosure of which is incorporated byreference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. Pat. No.8,918,190, entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” filed on Dec. 7, 2011, and U.S. Pat. No. 8,918,191,entitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction withBounded Titration,” filed on Dec. 7, 2011, the disclosures of which areincorporated by reference. Finally, the neurostimulator 12 can be usedto counter natural circadian sympathetic surge upon awakening and managethe risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, such as respectively described incommonly-assigned U.S. Pat. No. 8,923,964, entitled “ImplantableNeurostimulator-Implemented Method For Enhancing Heart Failure PatientAwakening Through Vagus Nerve Stimulation,” filed on Nov. 9, 2012, thedisclosure of which is incorporated by reference.

The VNS stimulation signal may be delivered as a therapy in amaintenance dose having an intensity that is insufficient to elicitundesirable side effects, such as cardiac arrhythmias. The VNS can bedelivered with a periodic duty cycle in the range of 2% to 89% with apreferred range of around 4% to 36% that is delivered as a low intensitymaintenance dose. Alternatively, the low intensity maintenance dose maycomprise a narrow range approximately at 17.5%, such as around 15% to25%. The selection of duty cycle is a tradeoff among competing medicalconsiderations. The duty cycle is determined by dividing the stimulationON time by the sum of the ON and OFF times of the neurostimulator 12during a single ON-OFF cycle. However, the stimulation time may alsoneed to include ramp-up time and ramp-down time, where the stimulationfrequency exceeds a minimum threshold (as further described infra withreference to FIG. 7).

FIG. 5 is a graph 70 showing, by way of example, the relationshipbetween the targeted therapeutic efficacy 73 and the extent of potentialside effects 74 resulting from use of the implantable neurostimulator 12of FIG. 1, after the patient has completed the titration process. Thegraph in FIG. 5 provides an illustration of the failure of increasedstimulation intensity to provide additional therapeutic benefit, oncethe stimulation parameters have reached the neural fulcrum zone, as willbe described in greater detail below with respect to FIG. 8. As shown inFIG. 5, the x-axis represents the duty cycle 71. The duty cycle isdetermined by dividing the stimulation ON time by the sum of the ON andOFF times of the neurostimulator 12 during a single ON-OFF cycle.However, the stimulation time may also include ramp-up time andramp-down time, where the stimulation frequency exceeds a minimumthreshold (as further described infra with reference to FIG. 7). Whenincluding the ramp-up and ramp-down times, the total duty cycle may becalculated as the ON time plus the ramp-up and ramp-down times dividedby the OFF time, ON time, and ramp-up and ramp-down times, and may be,e.g., between 15% and 30%, and more specifically approximately 23%. They-axis represents physiological response 72 to VNS therapy. Thephysiological response 72 can be expressed quantitatively for a givenduty cycle 71 as a function of the targeted therapeutic efficacy 73 andthe extent of potential side effects 74, as described infra. The maximumlevel of physiological response 72 (“max”) signifies the highest pointof targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty cyclerange 83 is a function 84 of the intersection 75 of the targetedtherapeutic efficacy 73 and the extent of potential side effects 74. Thetherapeutic operating points 82 can be expressed quantitatively for agiven duty cycle 81 as a function of the values of the targetedtherapeutic efficacy 73 and the extent of potential side effects 74 atthe given duty cycle shown in the graph 70 of FIG. 5. The optimaltherapeutic operating point 85 (“max”) signifies a tradeoff that occursat the point of highest targeted therapeutic efficacy 73 in light oflowest potential side effects 74 and that point will typically be foundwithin the range of a 5% to 30% duty cycle 81. Other expressions of dutycycles and related factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in a lowlevel maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally-mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μsecdelivers between 0.02 mA and 50 mA of output current at a signalfrequency of about 10 Hz, although other therapeutic values could beused as appropriate. In general, the stimulation signal delivered to thepatient may be defined by a stimulation parameter set comprising atleast an amplitude, a frequency, a pulse width, and a duty cycle.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation or configured to deliver anegligible or ineffective stimulation.

In another embodiment, as shown in FIG. 7, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97 and a ramp-down time 98 that respectively precede and follow theON time 92. Under this embodiment, the ON time 92 is considered to be atime during which the neurostimulator 12 is ON and delivering pulses ofstimulation at the full output current 96. Under this embodiment, theOFF time 95 is considered to comprise the ramp-up time 97 and ramp-downtime 98, which are used when the stimulation frequency is at least 10Hz, although other minimum thresholds could be used, and both ramp-upand ramp-down times 97, 98 last two seconds, although other time periodscould also be used. The ramp-up time 97 and ramp-down time 98 allow thestrength of the output current of each output pulse to be graduallyincreased and decreased, thereby avoiding deleterious reflex behaviordue to sudden delivery or inhibition of stimulation at a programmedintensity corresponding to the full output current 96.

Therapeutic vagus neural stimulation has been shown to providecardioprotective effects. Although delivered in a maintenance dosehaving an intensity that is insufficient to elicit undesirable sideeffects, such as cardiac arrhythmias, ataxia, coughing, hoarseness,throat irritation, voice alteration, or dyspnea, therapeutic VNS cannevertheless potentially ameliorate pathological tachyarrhythmias insome patients. Although VNS has been shown to decrease defibrillationthreshold, VNS has not been shown to terminate VF in the absence ofdefibrillation. VNS prolongs ventricular action potential duration, somay be effective in terminating VT. In addition, the effect of VNS onthe AV node may be beneficial in patients with AF by slowing conductionto the ventricles and controlling ventricular rate.

Neural Fulcrum Zone

As described above, autonomic regulation therapy results in simultaneouscreation of action potentials that simultaneously propagate away fromthe stimulation site in afferent and efferent directions within axonscomprising the cervical vagus nerve complex. Upon stimulation of thecervical vagus nerve, action potentials propagate away from thestimulation site in two directions, efferently toward the heart andafferently toward the brain. Different parameter settings for theneurostimulator 12 may be adjusted to deliver varying stimulationintensities to the patient. The various stimulation parameter settingsfor current VNS devices include output current amplitude, signalfrequency, pulse width, signal ON time, and signal OFF time.

When delivering neurostimulation therapies to patients, it is generallydesirable to avoid stimulation intensities that result in eitherexcessive tachycardia or excessive bradycardia. However, researchershave typically utilized the patient's heart rate changes as a functionalresponse indicator or surrogate for effective recruitment of nervefibers and engagement of the autonomic nervous system elementsresponsible for regulation of heart rate, which may be indicative oftherapeutic levels of VNS. Some researchers have proposed that heartrate reduction caused by VNS stimulation is itself beneficial to thepatient.

In accordance with some embodiments, a neural fulcrum zone isidentified, and neurostimulation therapy is delivered within the neuralfulcrum zone. This neural fulcrum zone corresponds to a combination ofstimulation parameters at which autonomic engagement is achieved but forwhich a functional response determined by heart rate change is nullifieddue to the competing effects of afferently and efferently-transmittedaction potentials. In this way, the tachycardia-inducing stimulationeffects are offset by the bradycardia-inducing effects, therebyminimizing side effects such as significant heart rate changes whileproviding a therapeutic level of stimulation. One method of identifyingthe neural fulcrum zone is by delivering a plurality of stimulationsignals at a fixed frequency but with one or more other parametersettings changed so as to gradually increase the intensity of thestimulation.

FIGS. 8A-8C provide illustrative charts reflecting the location of theneural fulcrum zone. FIG. 8A is a chart 800 illustrating a heart rateresponse in response to such a gradually increased intensity at a firstfrequency, in accordance with embodiments of the present invention. Inthis chart 800, the x-axis represents the intensity level of thestimulation signal, and the y-axis represents the observed heart ratechange from the patient's baseline basal heart rate observed when nostimulation is delivered. In this example, the stimulation intensity isincreased by increasing the output current amplitude.

A first set 810 of stimulation signals is delivered at a first frequency(e.g., 10 Hz). Initially, as the intensity (e.g., output currentamplitude) is increased, a tachycardia zone 851-1 is observed, duringwhich period, the patient experiences a mild tachycardia. As theintensity continues to be increased for subsequent stimulation signals,the patient's heart rate response begins to decrease and eventuallyenters a bradycardia zone 853-1, in which a bradycardia response isobserved in response to the stimulation signals. As described above, theneural fulcrum zone is a range of stimulation parameters at which thefunctional effects from afferent activation are balanced with ornullified by the functional effects from efferent activation to avoidextreme heart rate changes while providing therapeutic levels ofstimulation. In accordance with some embodiments, the neural fulcrumzone 852-1 can be located by identifying the zone in which the patient'sresponse to stimulation produces either no heart rate change or a mildlydecreased heart rate change (e.g., <5% decrease, or a target number ofbeats per minute). As the intensity of stimulation is further increasedat the fixed first frequency, the patient enters an undesirablebradycardia zone 853-1. In these embodiments, the patient's heart rateresponse is used as an indicator of autonomic engagement. In otherembodiments, other physiological responses may be used to indicate thezone of autonomic engagement at which the propagation of efferent andafferent action potentials are balanced to identify the neural fulcrumzone.

FIG. 8B is a chart 860 illustrating a heart rate response in response tosuch a gradually increased intensity at two additional frequencies, inaccordance with embodiments of the present invention. In this chart 860,the x-axis and y-axis represent the intensity level of the stimulationsignal and the observed heart rate change, respectively, as in FIG. 8A,and the first set 810 of stimulation signals from FIG. 8A is also shown.

A second set 820 of stimulation signals is delivered at a secondfrequency lower than the first frequency (e.g., 5 Hz). Initially, as theintensity (e.g., output current amplitude) is increased, a tachycardiazone 851-2 is observed, during which period, the patient experiences amild tachycardia. As the intensity continues to be increased forsubsequent stimulation signals, the patient's heart rate response beginsto decrease and eventually enters a mild heart rate reduction zone 854,in which a mild decrease in heart rate is observed in response to thestimulation signals. The low frequency of the stimulation signal in thesecond set 820 of stimulation signals limits the functional effects ofnerve fiber recruitment and, as a result, the heart response remainsrelatively limited. Although this low frequency stimulation results inminimal heart rate reduction, and, therefore, minimal side effects, thestimulation intensity is too low to result in effective recruitment ofnerve fibers and engagement of the autonomic nervous system. As aresult, a therapeutic level of stimulation is not delivered.

A third set of 830 of stimulation signals is delivered at a thirdfrequency higher than the first and second frequencies (e.g., 20 Hz). Aswith the first set 810 and second set 820, at lower intensities, thepatient first experiences a tachycardia zone 851-3. At this higherfrequency, the level of increased heart rate is undesirable. As theintensity is further increased, the heart rate decreases, similar to thedecrease at the first and second frequencies but at a much higher rate.The patient first enters the neural fulcrum zone 852-3 and then theundesirable bradycardia zone 853-3. Because the slope of the curve forthe third set 830 is much steeper than the first set 810, the region inwhich the patient's heart rate response is between 0% and −5% (e.g., theneural fulcrum zone 852-3) is much narrower than the neural fulcrum zone852-1 for the first set 810. Accordingly, when testing differentoperational parameter settings for a patient by increasing the outputcurrent amplitude by incremental steps, it can be more difficult tolocate a programmable output current amplitude that falls within theneural fulcrum zone 852-3. When the slope of the heart rate responsecurve is high, the resulting heart rate may overshoot the neural fulcrumzone and create a situation in which the functional response transitionsfrom the tachycardia zone 851-3 to the undesirable bradycardia zone853-3 in a single step. At that point, the clinician would need toreduce the amplitude by a smaller increment or reduce the stimulationfrequency in order to produce the desired heart rate response for theneural fulcrum zone 852-3.

FIG. 8C is a chart 880 illustrating mean heart rate response surfaces inconscious, normal dogs during 14 second periods of right cervical vagusVNS stimulation ON-time. The heart rate responses shown in z-axisrepresent the percentage heart rate change from the baseline heart rateat various sets of VNS parameters with the pulse width set at 250 μsec,the pulse amplitude ranging from 0 mA to 3.5 mA (provided by thex-axis), and the pulse frequency ranging from 2 Hz to 20 Hz (provided bythe y-axis). Curve 890 roughly represents the range of stimulationamplitude and frequency parameters at which a null response (i.e., 0%heart rate change from baseline) is produced. This null response curve890 is characterized by the opposition of functional responses (e.g.,tachycardia and bradycardia) arising from afferent and efferentactivation.

Titration Process

Several classes of implantable medical devices provide therapy usingelectrical current as a stimulation vehicle. When such a systemstimulates certain organs or body structures like the vagus nerve,therapeutic levels of electrical stimulation are usually not welltolerated by patients without undergoing a process known as titration.Titration is a systematic method of slowly increasing, over time,stimulation parameters employed by an implanted device to deliverstimulation current until therapeutic levels become tolerated by thepatient.

FIG. 9 is a flow diagram showing a method for delivering vagus nervestimulation therapy 900, in accordance with embodiments of the presentinvention. A titration process is used to gradually increase thestimulation intensity to a desired therapeutic level. If the stimulationintensity is increased too quickly before the patient is fullyaccommodated to the stimulation signal, the patient may experienceundesirable side effects, such as coughing, hoarseness, throatirritation, or expiratory reflex. The titration process graduallyincreases stimulation intensity within a tolerable level, and maintainsthat intensity for a period of time to permit the patient to adjust toeach increase in intensity, thereby gradually increasing the patient'sside effect tolerance zone boundary to so as to accommodate subsequentincreases in intensity. The titration process continues until adequateadaptation is achieved. In preferred embodiments, the titration processis automated and is executed by the implanted device without manualadjustment of the stimulation intensity by the subject or health careprovider. As will be described in greater detail below, adequateadaptation is a composite threshold comprising one or more of thefollowing: an acceptable side effect level, a target intensity level,and a target physiological response. In preferred embodiments, adequateadaption includes all three objectives: an acceptable side effect level,a target intensity level, and a target physiological response.

As described above, it may be desirable to minimize the amount of timerequired to complete the titration process so as to begin delivery ofthe stimulation at therapeutically desirable levels, particularly whenthe patient is being treated for an urgent condition such as CHF. Inaddition, it is desirable to utilize a maintenance dose intensity at theminimum level required to achieve the desired therapeutic effect. Thiscan reduce power requirements for the neurostimulator and reduce patientdiscomfort.

It has been observed that a patient's side effect profile is moresensitive to the stimulation output current than to the otherstimulation parameters, such as frequency, pulse width, and duty cycle.As a result, accommodation to the stimulation output current is aprimary factor in completing the titration process. It has also beenobserved that if the other stimulation parameters are maintained at alevel below the target levels, the output current can be increased tohigher levels without eliciting undesirable side effects that would beresult when the other parameters are at the target level. As a result,increasing the target output current while maintaining the otherstimulation parameters (pulse width in particular) at reduced levels canresult in a faster accommodation and shorter overall titration time thanwould be achieved by attempting to increase the output current whilestimulating at the target pulse width.

In step 901, a stimulation system 11, including a neurostimulator 12, anerve stimulation lead assembly 13, and a pair of electrodes 14, isimplanted in the patient. In step 902, the patient undergoes an optionalpost-surgery recovery period, during which time the surgical incisionsare allowed to heal and no VNS therapy occurs. This period may last,e.g., two weeks post surgery. In step 903, the stimulation therapyprocess is initiated. During this process, VNS therapy is titrated byadjusting one or more of the stimulation parameters, including outputcurrent, pulse width, signal frequency, and duty cycle, as will bedescribed in greater detail below. Completion of the titration processdetermines the stimulation intensity to be used for subsequentmaintenance doses delivered in step 904. These maintenance doses may beselected to provide the minimum stimulation intensity necessary toprovide the desired therapeutic result.

FIG. 10 is a flow diagram illustrating a titration process 1000 inaccordance with embodiments of the present invention. When firstinitiating the titration process, the neurostimulator 11 is configuredto generate a stimulation signal having an initial stimulation parameterset. The initial parameter set may comprise an initial output current,an initial frequency, an initial pulse width, and an initial duty cycle.The various initial parameter settings may vary, but may be selected sothat one or more of the parameters are set at levels below a predefinedtarget parameter set level, such that the titration process is used togradually increase the intensity parameters to achieve adequateadaptation. In some embodiments, the initial frequency is set at thetarget frequency level, while the initial output current, initial pulsewidth, and initial duty cycle are set below their respective targetlevels. In one embodiment, the target parameter set comprises a 10 Hzfrequency, 250 μsec pulse width, a duty cycle of 14 sec ON and 1.1minutes OFF, and an output current of between 1.5 mA-3.0 mA (e.g., 2.5mA for right side stimulation and 3.0 mA for left side stimulation), andthe initial parameter set comprises 10 Hz frequency, 130 μsec pulsewidth, a duty cycle of 14 sec ON and 1.1 minutes OFF, and an outputcurrent of between 0.25 mA-0.5 mA. In other embodiments, the targetparameter set includes a 5 Hz frequency is used instead of a 10 Hzfrequency.

In step 1001, the stimulation system delivers stimulation to thepatient. If this is the first titration session, then the stimulationwould be delivered with the initial stimulation parameter set describedabove. If this is a subsequent titration session, then the stimulationintensity would remain at the same level at the conclusion of theprevious titration session.

In step 1002, the output current is gradually increased until thestimulation results in an intolerable side effect level, the targetoutput current (e.g., 2.5 mA) is reached, or adequate adaptation isachieved. As described above, adequate adaptation is a compositethreshold comprising one or more of the following: an acceptable sideeffect level, a target intensity level, and a target physiologicalresponse. In accordance with some embodiments, the target physiologicalresponse comprises a target heart rate change during stimulation. Thepatient's heart rate may be monitored using an implanted or externalheart rate monitor, and the patient's heart rate during stimulation iscompared to the patient's baseline heart rate to determine the extent ofheart rate change. In accordance with some embodiments, the target heartrate change is a heart rate change of between 4% and 5%. If at any pointduring the titration process 1000 adequate adaptation is achieved, thetitration process ends and the stimulation intensity which resulted inthe adequate adaptation is used for ongoing maintenance dose therapydelivery.

The output current may be increased in any desired increment, but smallincrements, e.g., 0.1 mA or 0.25 mA, may be desirable so as to enablemore precise adjustments. In some cases, the output current incrementsmay be determined by the neurostimulator's maximum control capability.During the initial titration sessions, it is likely that the patient'sside effect tolerance zone boundary will be reached well before theoutput current reaches the target level or adequate adaptation isachieved. At decision step 1003, if the target output current has notbeen achieved but the maximum tolerable side effects have been exceeded,the process proceeds to step 1004.

In step 1004, the output current is reduced one increment to bring theside effects within acceptable levels. In addition, the frequency isreduced. In embodiments in which the initial frequency was 10 Hz, instep 1004, the frequency may be reduced, e.g., to 5 Hz or 2 Hz.

Next, in step 1005, the output current is gradually increased again atthe reduced frequency level until the stimulation results in anintolerable side effect level or the target output current (e.g., 2.5mA) is reached. At decision step 1006, if the target output current hasnot been reached but the maximum tolerable side effects have beenexceeded, the process proceeds to step 1007.

In step 1007, the titration session is concluded. The stimulation systemmay be programmed to continue delivering the stimulation signal at thelast parameter settings achieved prior to conclusion of the titrationsession. After a period of time, another titration session may beinitiated and the process returns to step 1001. This can be any periodof time sufficient to permit the patient to adjust to the increasedstimulation levels. This can be, for example, as little as approximatelytwo or three days, approximately one to two weeks, approximately four toeight weeks, or any other desired period of time.

In some embodiments, the titration sessions are automatically initiatedby the stimulation system or initiated by the patient without requiringany intervention by the health care provider. This can eliminate theneed for the patient to schedule a subsequent visit to the health careprovider, thereby potentially reducing the total amount of time neededfor the titration process to complete. In these embodiments, thestimulation system includes a physiological monitor, e.g., an implantedheart rate sensor, that communicates with the stimulation system'scontrol system to enable the control system to detect when the targetphysiological response has been achieved and conclude the titrationprocess. The stimulation system could in addition or alternativelyinclude a patient control input to permit the patient to communicate tothe control system that the acceptable side effect level has beenexceeded. This control input may comprise an external control magnetthat the patient can swipe over the implanted neurostimulator, or otherinternal or external communication device that the patient can use toprovide an input to the control system. In these automatically initiatedtitration sessions, the stimulation system may be configured to wait aperiod of time after completing one session before initiating the nextsession. This period of time may be predetermined, e.g., two or threedays.

Returning to decision step 1006, if the target output current has notbeen reached but the maximum tolerable side effects have been exceeded,the process proceeds to step 1008. In step 1008, the output current isreduced one increment to restore an acceptable side effect condition,and the frequency is gradually increased until the stimulation resultsin an intolerable side effect level or the target frequency (e.g., 10Hz) is reached. At decision step 1009, if the target frequency has notbeen reached but the maximum tolerable side effects have been exceeded,the frequency is reduced to restore an acceptable side effect level andthe process proceeds to step 1007. Again, in step 1007, the currenttitration session is concluded and the stimulation system may beprogrammed to continue delivering the stimulation signal at the lastparameter settings achieved prior to conclusion of the titrationsession.

At decision step 1009, if the target frequency has been reached beforethe maximum tolerable side effects have been exceeded, the processproceeds to step 1010 and the duty cycle is gradually increased untilthe stimulation results in an intolerable side effect level or thetarget duty cycle (e.g., 14 sec ON and 1.1 min OFF) is reached, at whichpoint the process proceeds to step 1007 and the titration session isconcluded and ongoing stimulation delivered at the last intensityeliciting acceptable side effect levels.

Returning to decision step 1003, if the target output current has beenachieved before the maximum tolerable side effects are exceeded, theprocess proceeds to step 1011. In step 1011, the pulse width isgradually increased until the stimulation results in an intolerable sideeffect level or the target pulse width (e.g., 250 μsec) is reached. Insome embodiments, before step 1011, the output current is reduced (e.g.,by up to 50%), and the pulse width may be increased in step 1011 at thatreduced output current. After the target pulse width is achieved in step1012, the output current may be restored to the target output current.In other embodiments, the output current may be reduced (or may beretained at the reduced level established prior to step 1011, asdescribed above), and the frequency and duty cycle are graduallyincreased in step 1013 (described below) at that reduced output current.This reduction in output current after achieving the target outputcurrent may enable the patient to maintain tolerability with increasingpulse width, frequency, and duty cycle in subsequent titration steps.

At decision step 1012, if the target pulse width has not been achievedbefore the maximum tolerable side effects have been exceeded, the pulsewidth is reduced to restore an acceptable side effect level and theprocess proceeds to step 1007. Again, in step 1007, the currenttitration session is concluded.

If at decision step 1012, the target pulse width has been achievedbefore the maximum tolerable side effects have been exceeded, theprocess proceeds to step 1013. In step 1013, the frequency and dutycycle are increased until the stimulation results in an intolerable sideeffect level or the target frequency and target duty cycle are reached.The frequency and duty cycle can be increased in step 1013simultaneously, sequentially, or on an alternating basis.

At decision step 1014, if the target frequency and target duty cyclehave not been achieved before the maximum tolerable side effects havebeen exceeded, the pulse width and/or frequency are reduced to restorean acceptable side effect level and the process continues to step 1007and the titration session is concluded.

At decision step 1014, if the target pulse width and target frequencyhave been achieved before the maximum tolerable side effects have beenexceeded, all of the stimulation parameters will have reached theirtarget levels and the titration process concludes at step 1015. Thestimulation therapy may proceed with the maintenance dose at the targetstimulation levels.

In some embodiments, in step 1004, instead of reducing the frequency inorder to facilitate increase of the output current, the pulse width maybe reduced. For example, embodiments where the target pulse width is 250μsec, the pulse width may be reduced, e.g., to 150 μsec or less. Then,the method proceeds to step 1005, in which the output current isgradually increased again at the reduced pulse width level until thestimulation results in an intolerable side effect level or the targetoutput current (e.g., 2.5 mA) is reached.

Therapy can also be autonomously titrated by the neurostimulator 12 inwhich titration progressively occurs in a self-paced, self-monitoredfashion. The progression of titration sessions may occur on anautonomous schedule or may be initiated upon receipt of an input fromthe patient. Ordinarily, the patient 10 is expected to visit hishealthcare provider to have the stimulation parameters stored by theneurostimulator 12 in the recordable memory 29 reprogrammed using anexternal programmer. Alternatively, the neurostimulator 12 can beprogrammed to automatically titrate therapy by up titrating the VNSthrough periodic incremental increases as described above. The titrationprocess 1000 will continue until the ultimate therapeutic goal isreached.

Following the titration period, therapeutic VNS, as parametricallydefined by the maintenance dose operating mode, is delivered to at leastone of the vagus nerves. The stimulation system 11 delivers electricaltherapeutic stimulation to the cervical vagus nerve of a patient 10 in amanner that results in creation and propagation (in both afferent andefferent directions) of action potentials within neuronal fibers ofeither the left or right vagus nerve independent of cardiac cycle.

In a further embodiment, the sensed heart rate data can be used toanalyze therapeutic efficacy and patient condition. For instance,statistics could be determined from the sensed heart rate, eitheronboard by the neurostimulator 12 or by an external device, such as aprogramming computer following telemetric data retrieval. The sensedheart rate data statistics can include determining a minimum heart rateover a stated time period, a maximum heart rate over a stated timeperiod, an average heart rate over a stated time period, and avariability of heart rate over a stated period, where the stated periodcould be a minute, hour, day, week, month, or other selected timeinterval. Still other uses of the heart rate sensor 31 and the sensedheart rate data are possible.

FIG. 11A is a simplified block diagram of an implanted neurostimulationsystem 1100 in accordance with embodiments of the present invention. Theimplanted neurostimulation system 1100 comprises a control system 1102comprising a processor programmed to operate the system 1100, a memory1103, an optional physiological sensor 1104, and a stimulation subsystem1106. The physiological sensor 1104 may be configured to monitor any ofa variety of patient physiological signals and the stimulation subsystem1106 may be configured to deliver a stimulation signal to the patient.In one example, the physiological sensor 1104 comprises an ECG sensorfor monitoring heart rate and the stimulation subsystem 1106 comprises aneurostimulator 12 programmed to deliver ON-OFF cycles of stimulation tothe patient's vagus nerve.

The control system 1102 is programmed to activate the neurostimulator 12to deliver varying stimulation intensities to the patient and to monitorthe physiological signals in response to those stimulation signals.

The external programmer 1107 shown in FIG. 11A may be utilized by aclinician or by the patient for communicating with the implanted system1100 to adjust parameters, activate therapy, retrieve data collected bythe system 1100 or provide other input to the system 1100. In someembodiments, the external programmer 1107 may be configured to programthe implanted system 1100 with a prescribed time or window of timeduring which titration sessions may be initiated. This can be used toprevent a titration session from occurring at night when the patient'ssleep is likely to be disturbed by the increase in stimulation intensityand resulting side effects.

Patient inputs to the implanted system 1100 may be provided in a varietyof ways. The implanted system 1100 may include a patient input sensor1105. As described above, a patient magnet 1130 may be used to provideexternal input to the system 1100. When the patient magnet 1130 isplaced on the patient's chest in close proximity to the implanted system1100, the patient input sensor 1105 will detect the presence of themagnetic field generated by the patient magnet 1130 and provide acontrol input to the control system 1102. The system 1100 may beprogrammed to receive patient inputs to set the time of day during whichtitration sessions are to be initiated.

In other embodiments, the patient input sensor 1105 may comprise amotion sensor, such as an accelerometer, which is configured to detecttapping on the surface of the patient's chest. The patient may usefinger taps in one or more predetermined patterns to provide controlinputs to the implanted system 1100. For example, when the motion sensordetects three rapid taps to the patient's chest, that may trigger anoperation on the implanted system 1100 (e.g., to initiate a titrationsession). Alternatively, if the motion sensor detects a predeterminedpattern of taps during a titration session, the implanted system 1100will interpret those taps as a patient input indicating that thepatient's tolerance zone boundary has been exceeded.

In other embodiments, the patient input sensor 1105 may comprise anacoustic transducer or other sensor configured to detect acousticsignals. The system 1100 may be programmed to interpret the detection ofcertain sounds as patient inputs. For example, the patient may utilizean electronic device, such as a smartphone or other portable audiodevice, to generate one or more predetermined sequences of tones. Thesystem 1100 may be programmed to interpret each of these sequences oftones as a different patient input.

In other embodiments, the patient input sensor 1105 may be configured todetect when a patient is coughing, which can be interpreted by thesystem 1100 as an indication that the increased stimulation intensityexceeds the patient's tolerance zone boundary. The coughing could bedetected by an accelerometer to detect movement of the patient's chest,an acoustic transducer to detect the sound of the patient's coughing, orboth.

The titration of the stimulation signal delivery and the monitoring ofthe patient's physiological response (e.g., heart rate) may beadvantageously implemented using control system in communication withboth the stimulation subsystem 1106 and the physiological sensor 1104,such as by incorporating all of these components into a singleimplantable device. In accordance with other embodiments, the controlsystem may be implemented in a separate implanted device or in anexternal programmer 1120 or other external device, as shown in FIG. 11B.The external programmer 1120 in FIG. 11B may include a control system1112 and be utilized by a clinician or by the patient for adjustingstimulation parameters. The external programmer 1120 is in wirelesscommunication with the implanted medical device 1110, which includes thestimulation subsystem 1116. In the illustrated embodiment, thephysiological sensor 1114 is incorporated into the implanted medicaldevice 1110, but in other embodiments, the sensor 1114 may beincorporated into a separate implanted device, may be providedexternally and in communication with the external programmer 1120, ormay be provided as part of the external programmer 1120. The implantedmedical device 1110 may include a memory 1113 that may store informationin preparation for a transmission to the external programmer 1120.

Personalized Titration Via Parametric Modification

Titration is a method of varying over time stimulation parametersemployed by an implanted device to deliver stimulation current, untiltherapeutic levels become tolerated by the patient. Embodiments providedabove describe automated titration processes used to gradually increasethe stimulation intensity to a desired therapeutic level. Duringperiodic titration sessions, the stimulation intensity is increaseduntil the maximum tolerable side effects are exceeded, at which pointthe stimulation intensity is reduced to a tolerable level and thepatient is provided with a period of time to adapt to the new intensitylevels before the next titration session is initiated. In someembodiments, the titration sessions may occur on a regular schedule(e.g., every two weeks), with an acclimation interval in between eachtitration session during which time stimulation at a tolerable intensitylevel is delivered. However, patients adapt to increased stimulationintensity levels at different rates, so the minimum acclimation intervalrequired before the next titration session can successfully be initiatedvaries. In other embodiments, parameters other than or in addition tothe acclimation interval may be adjusted based on the actual adaptionexperienced by the patient. The parameters that might be adjustedinclude, for example: current amplitude, pulse width, frequency, and OFFtime.

In accordance with some embodiments of the present invention, anautomated titration process is provided which utilizes an acclimationinterval between titration sessions that may be adjusted based on thepatient's response to the stimulation. FIG. 12 illustrates a titrationprocess 1200 with a variable acclimation interval. Steps 1201-1203 aresimilar to steps 901-903 illustrated in FIG. 9 and described above.However, in step 1204, an outcome measure for the titration sessions isanalyzed. In step 1205, the acclimation interval between subsequenttitration sessions is adjusted based on the analyzed outcome measure. Ifthe outcome measure indicates that the patient is adapting to thestimulation at a slower than expected rate, then the acclimationinterval may be increased to provide the patient with additional time torecover and adapt to each set of increased stimulation intensities.Conversely, if the outcome measure indicates that the patient isadapting to the stimulation at a faster than expected rate, then theacclimation interval may be decreased to accelerate the adaption processand reduce the overall time required to complete the titration processand achieve a tolerable therapeutic maintenance dose level.

Any of a variety of outcome measures may be used. In some embodiments,the outcome measure is the patient's tolerance of a targeted increase inone or more of the stimulation parameters. For example, if the patientis unable to tolerate any increase in stimulation output current (orstimulation parameter) over the course of two or more titration sessionsseparated by a default acclimation interval (e.g., two weeks), it may beconcluded that the patient is adapting to the stimulation at a slowerthan expected rate. In response, the acclimation interval betweensubsequent titration sessions may be increased (to, e.g., three or moreweeks). If the patient continues to be incapable of tolerating anyincrease in stimulation output current in subsequent titration sessions,then the acclimation interval may be increased again (to, e.g., four ormore weeks).

In some cases, the patient may initially adapt to the increasedstimulation intensity at a slower than expected rate, but after theacclimation interval is increased and subsequent titration sessions aresuccessful at achieving the desired outcome measure, the patient'sadaptation may accelerate, thereby permitting reduction of theacclimation interval back to the initial interval length. Accordingly,if the patient begins to adapt to the titration sessions after anincrease in the acclimation interval, the system 1100 may be programmedto gradually reduce the acclimation interval in subsequent titrationsessions.

In various embodiments described above, after a titration session isterminated, the system may be programmed to continue deliveringstimulation at the last parameter settings achieved prior to conclusionof the titration session at an intensity just below the patient'stolerance zone boundary. This stimulation is delivered at this constantintensity until the next titration session is initiated. In some cases,patients are capable of enduring stimulation intensities just past thetolerance zone boundary for limited periods of time. The intensitylevels just past the tolerance zone boundary may be considered by thepatient as “moderately tolerable.” Patients may be willing to endurestimulation at the moderately tolerable levels for limited periods oftime if it results in acceleration of the adaption process.

In accordance with some embodiments, after a titration session isconcluded or at any desired periodicity during the acclimation interval,an elevated stimulation session may be initiated, during which timestimulation at moderately tolerable levels exceeding the tolerance zoneboundary is delivered. This elevated stimulation session may continuefor any desired period of time, such as, e.g., several minutes orseveral hours, after which point the stimulation intensity will bereduced to a sustained stimulation intensity level below the tolerancezone boundary. In some embodiments, the elevated stimulation session maycontinue for less than one day, while the sustained stimulation isdelivered for a period greater than one day, or the elevated stimulationsession may continue for less than six hours, while the sustainedstimulation is delivered for a period greater than one week. Any desiredperiods of time may be used.

Interactive Training Sessions

Various methods are described herein for titrating stimulation bygradually increasing stimulation intensity until the patient's tolerancezone boundary is reached or exceeded. In accordance with embodiments ofthe present invention, systems and methods are provided for performinginteractive training sessions in clinic for patients about to undergotitration on an ambulatory basis. The methods permit clinicians tocreate a series of stimulation intensities (ranging from un-noticeableto noticeable but tolerable to intolerable), the patient's response toeach stimulation, and the implanted device's response to patient inputs.

The implanted medical device 1100 may be used in conjunction with anexternal clinician programmer 1107 and patient input device (e.g.,patient magnet 1130 or wireless-communications-enabled patient controldevice), to perform the titration processes on an ambulatory basis asdescribed above, but is also programmed to execute in a training mode.This training mode may be initiated by the clinician using the clinicianprogrammer 1107 while the patient is physically in the clinic fortreatment and training. The training mode may be similar to thetitration sessions described above, except that the increasingstimulation is initiated by the clinician using the programmer 1107 orautomatically on an accelerated schedule. When the stimulation intensityreaches the patient's tolerance zone boundary, the patient can use anyof the herein described methods for providing a patient input to thedevice 1100 to indicate that the tolerance zone boundary has beenreached. When in training mode, the device 1100 may also transmit to theclinician programmer 1107 information regarding the stimulation beingdelivered. The programmer 1107 may include a display which permits theclinician to observe the increasing intensity and receive a report ofthe intensity level that elicited the patient input indicating that thetolerance zone boundary was reached. The display on the programmer 1107may also be used to display feedback or instructions to the patient.

The clinician may run the training mode multiple times so that thepatient may become proficient at recognizing stimulation levels that arenoticeable but tolerable, and distinguishing those tolerable levels fromthe truly intolerable stimulation levels. This can also provide trainingfor the patient in the proper use of the patient input device. In someembodiments, the programmer 1107 may be used to select the stimulationparameter to be increased (e.g., output current, frequency, pulse width,or duty cycle), so that the patient and clinician can observe thedifferent responses that may be elicited depending on the parameterbeing adjusted. In some embodiments, the programmer 1107 may beconfigured to pause the titration algorithm to hold the stimulation at asingle level. This may be useful for facilitating a tolerance zoneassessment by providing the patient additional time to experience thestimulation. The programmer 1107 may also be used to terminate thetraining mode and return the device 1100 to its normal ambulatory mode,during which the desired ambulatory titration process may be performed.

The training mode may also comprise an algorithm that sequencesstimulation changes based on the training mode parameters programmed bythe clinician. Stimulation may be altered on a highly accelerated timescale in order to move the patient from tolerable tonoticeable-but-tolerable to intolerable stimulation levels within thenormal office follow-up period. This accelerated time scale may be, forexample, five, ten or fifteen minutes for all training. This is incontrast to the ambulatory mode titration process that seeks to advancetherapy levels without the patient exceeding the tolerance-zoneboundary. Having the patient experience all three tolerance phases in asingle clinic visit can provide valuable patient training, resulting inaccelerated adaptation speed.

The system 1100 may be programmed with an autonomous monitor to ensurethat the training mode terminates automatically after a certain periodhas elapsed, even in the absence of a termination input from theclinician programmer. For example, the system 1100 may be programmed toautomatically time-out and terminate the training mode 24 hours afterinitiation. After this automatic time-out, the system 1100 mayautomatically initiate the ambulatory mode.

As a result, the system may enable patients to experience stimulationlevels (usually following a stimulation increase) that may beunacceptable. Patients may also learn how to effectively deal with theintolerance through the use of the external patient input device.Clinicians can learn how individual patients react to variousstimulation levels and the patients' cognitive ability to deal withunacceptable stimulation autonomously. Clinicians may also gain a senseof stimulation increases that an individual patient can tolerate andadjust the ambulatory titration algorithm accordingly.

T-Wave Alternans Target

T-wave alternans (TWA) is a periodic beat-to-beat variation in theamplitude or shape of the T-wave of a subject's ECG. TWA is a marker ofcardiac electrical instability, and has been used for arrhythmia riskstratification. Experiments have indicated that TWA is fundamentallylinked to vulnerability to ventricular fibrillation (VF) and is anestablished market of risk for sudden cardiac death (SCD) in patientswith diverse cardiovascular diseases, including heart failure. Inaccordance with embodiments of the present invention, TWA may be used inplace of or in addition to the heart rate monitoring described above inconnection with the titration of stimulation and determination ofoptimal stimulation parameters for autonomic regulation therapy (ART).Analysis of TWA in heart failure patients receiving ART has shown arelationship between stimulation current amplitude and TWA.

As previously described, when delivering neurostimulation therapies topatients, it is generally desirable to avoid stimulation intensitiesthat result in either excessive tachycardia or excessive bradycardia. Invarious embodiments above, a patient's heart rate response or a targetstimulation parameter such as output current may be utilized whentitrating stimulation and determining optimal stimulation parameters. Inother embodiments, a patient's TWA may be used instead of or in additionto the heart rate response and target output current during stimulationtitration. An implantable ART system which includes a sensor formonitoring cardiac rhythm may be used. The implanted device cancalculate TWA at various points during the titration period. This TWAcalculation may be performed using methods similar to publishedalgorithms, as will be described in greater detail below. The systemcould first establish a TWA baseline value monitored during thepost-implant period (e.g. 1-2 weeks after implantation) before theinitiation of stimulation. The titration process may then beautomatically performed by the implanted device, but instead oftitrating to a target output current, as described above, the devicewould titrate stimulation intensity until a target TWA change from theestablished baseline TWA or target TWA level is observed. Once thattarget TWA change is achieved, the titration process is completed andthe device may continue delivering the autonomic regulation therapy atthe stimulation parameter settings that resulted in the target TWAchange. In some embodiments, after the titration is complete and thetherapeutic levels of stimulation are delivered for some period of time,the device may periodically monitor TWA levels and adjust stimulation asneeded to maintain the target TWA change or target TWA level.

Various methods may be used for determining the patient's TWA. Oneapproach is to utilize a modified moving average analysis, as describedin Nearing et al., “Modified Moving Average Analysis of T-Wave Alternansto Predict Ventricular Fibrillation with High Accuracy,” J. Appl.Physiol. 92: 541-549 (2002), the disclosure of which is incorporated byreference herein in its entirety. This approach involves constructingmodified moving average computed beats by averaging alternate ECG beats.A weighted moving average is applied to limit the contribution of anyone beat. The alternans estimate for any ECG segment is then determinedas the maximum difference between A and B modified moving averagecomputed beats within the ST segment and T-wave region. Another approachis to utilize a spectral analysis method of analyzing TWA in thefrequency domain, as described in Smith et al., “Electrical alternansand cardiac electrical instability,” Circulation 77, No. 1, 110-121(1988), the disclosure of which is incorporated by reference herein inits entirety. This approach utilizes a spectral analysis procedure toquantify the degree and statistical significance of waveform alternationpresent in the magnitude of the three orthogonal-lead ECG.

The ECG signal may be obtained using a sensor provided in a variety oflocations. In some embodiments, the ECG sensor is incorporated into thehousing of the implanted neurostimulator, or the ECG may be detectedusing implanted ECG leads coupled to the implanted neurostimulator. Inother embodiments, ECG may be monitored using an external device whichis in communication with the implanted neurostimulator. The calculationof TWA and determination of change from the baseline TWA may beperformed by either the external or implanted devices.

The target TWA change from the baseline TWA or target TWA value may beany value that corresponds with the desired therapeutic effect. In someembodiments, the target TWA change from the baseline TWA may be in therange of approximately −20 μV to approximately −30 μV, e.g., a targetTWA decrease of 25 μV. In some embodiments, the target TWA change fromthe baseline TWA may be a decrease of at least 10 μV.

In one experiment, subjects were implanted with a VNS therapy system(DEMIPULSE Model 103 pulse generator and PERENNIAFLEX Model 304 lead,both from Livallova PLC of Houston, Tex.) with randomized lead placementon either the right (N=12) or left cervical vagus nerve (N=11). Thepulse generator was activated at 15±3 days after implantation. Allpatients were initially stimulated at a pulse width of 130 μs and apulse frequency of 10 Hz, continuous cyclic 14-sec active (ON) and66-sec inactive (OFF) to produce a duty cycle of 18%; 1,080 cycles/day.Stimulation parameters were systematically adjusted during periodicclinic visits over a 10-week titration period to a pulse width of 250μs, a pulse frequency of 10 Hz, and target output current amplitude of1.5-3.0 mA. VNS activation and inactivation periods were unrelated tothe cardiac cycle (i.e., open loop), so no intracardiac sensing lead wasused. During titration sessions, VNS intensity was gradually increasedin 0.25 mA steps with the use of a radiofrequency programmer (Model 250programming system from Livallova PLC) to levels that produced acuteVNS-related side effects (referred to as the “VNS tolerance zoneboundary”), such as activation of the expiratory reflex (mild cough) ormoderate heart rate reduction during the VNS-active phase. When the VNStolerance zone boundary was established by evidence of expiratory reflexactivation or heart rate reduction, the output current was reduced by ≥1output current step (0.25 mA) to ensure that the therapy was welltolerated. During the 10-week titration period, the VNS stimulationintensity was progressively increased to an average output current of2.0±0.1 mA (for left side implantation patients: 2.2±0.2 mA; for rightside implantation patients: 1.8±0.2 mA). Continuous cyclic stimulationwas maintained at a tolerable level throughout the titration period andthe 12-month follow-up period. Effects of low intensity (<2 mA, n=9) andhigh intensity (≥2 mA, n=14) stimulation levels were compared.

Ambulatory ECG 24-hour recordings were made using an externally-wornHolter monitor at baseline and after six and twelve months of chronictherapy. Measurements of TWA, HRT, HRV, ventricular tachycardia (VT)incidence, and heart rate were performed by an investigator.

Peak TWA was quantified from standard precordial leads V₁ and V₅ and aVFin 24-hour recordings with the Modified Moving Average (MMA) method, asdescribed in the Nearing publication cited above. Limb leads were notrecorded, as they are prone to motion artifact associated with dailyactivities. The MMA method employs the noise-rejection principle ofrecursive averaging. The maximum TWA level throughout the recording isreported as the TWA value for that patient. As established in patientswith heart disease, a TWA threshold level of greater than or equal to 47μV was defined in this study as an abnormal TWA test, and greater thanor equal to 60 μV was defined as markedly abnormal.

In the 23 patients that were followed up for twelve months, mean TWA was70±4.9 at baseline (left side: 73±7.3 μV; right side: 68±8.4 μV). PeakTWA in the pooled cohort (n=23) did not improve after six months ofcontinuous cyclic stimulation, but improved significantly after twelvemonths of therapy (by −20±4.5 μV, p=0.0002). At baseline, 83% (19 of 23)of patients had TWA of greater than or equal to 60 μV, the threshold forstrongly abnormal levels. At six months, 78% (18 of 23) had TWA ofgreater than or equal to 60 μV. At twelve months, 65% (15 of 23) had TWAof greater than or equal to 60 μV. No patient achieved TWA less than 47μV at baseline or during the follow up year. Improvement in TWA wassimilar with both left-sided and right-sided stimulation. Patients whowere titrated to a low intensity of stimulation (less than 2.0 mA, n=9)did not show a significant improvement in TWA at either six months ortwelve months. Patients who were titrated to a higher intensity ofstimulation (greater than or equal to 2.0 mA, n=14) showed a significantimprovement in TWA at twelve months (by −23±5.9 μV, p=0.002).

FIG. 13 is a scatter plot 1300 illustrating stimulation output currentand corresponding T-wave alternans changes from baseline. Thestimulation was delivered at a frequency of 10 Hz, a pulse width of250-μsec, and a duty cycle of 18%. At stimulation output currents below2.0 mA, all but one of the data points in plot 1300 are indicative of anundesirable increase in TWA from the baseline TWA. Accordingly, duringthe titration process, if an increase in TWA from the baseline TWA isobserved, the device may be programmed to increase the output current(or other stimulation intensity parameter) until the target TWA changeis achieved. At stimulation output currents of 2.0 mA and above, all butthree of the data points in plot 1300 are indicative of a decrease inTWA from the baseline TWA. When a decrease in TWA from the baseline TWAis observed, it may be concluded that the stimulation intensity isachieving a positive therapeutic effect. The device may be programmed toterminate the titration process and begin delivering ongoing therapy atthe stimulation intensity that produced the desired decrease in TWA frombaseline.

FIGS. 14A-14B are assessments of TWA using the MMA method in a singlerepresentative patient with heart failure. The patient's ECG recordingswere separated into alternating A beats and B beats, and then an averagewas taken of each to produce an average A Beat signal 1401 and anaverage B Beat signal 1402. These signals were superimposed to determinethe TWA. FIG. 14A illustrates the QRS-aligned superimposed A Beat 1401 aand B Beat 1402 a taken at baseline, resulting in a TWA of 97 μV,calculated by performing a time-dependent difference between the curvesand calculating the maximum value in the T-wave period. This TWA levelof 97 μV is greater than the 60 μV threshold for strongly abnormallevels. FIG. 14B illustrates the QRS-aligned superimposed A Beat 1401 band B Beat 1402 b taken after twelve months of therapy, resulting in aTWA of 42 μV, which is less than the 47 μV threshold for abnormallevels. As can be seen in FIGS. 14A-14B, the patient's TWA levelsexperienced a significant decrease after twelve months of VNS therapy.

Heart rate turbulence (HRT) is an indicator of baroreflex sensitivity.In this experiment, various HRT parameters were measured for thepatients at baseline and after twelve months of VNS therapy. The HRTparameter turbulence onset (TO) calculates the initial briefacceleration of sinus rate after a premature ventricular contraction(PVC). The HRT parameter turbulence slope (TS) characterizes thesubsequent heart rate deceleration after the PVC.

FIGS. 15A-15B show HRT response to the VNS stimulation therapy over thetwelve month period in a representative patient. FIG. 15A shows the R-Rinterval in msec (y-axis) as a function of time (x-axis, showing thebeat number), taken at baseline, prior to implantation of the pulsegenerator. FIG. 15B shows the R-R interval taken after twelve months ofVNS therapy. The TO taken at baseline was not statistically differentthan the TO taken at either six or twelve months. However, in FIG. 15A,the baseline HRT turbulence slope (TS) 1501 a was 5.02 msec, and in FIG.15B, the HRT TS 1501 b had nearly doubled to 9.71 msec. This increase isindicative of significantly improved baroreceptor sensitivity.

FIG. 16 is a bar chart 1600 illustrating the TWA magnitude levels (inμV) taken at baseline, at six months, and at twelve months for subjectsreceiving low intensity stimulation (pulse amplitude less than 2.0 mA),subjects receiving high intensity stimulation (pulse amplitude greaterthan or equal to 2.0 mA), and overall for all subjects. In the fifteenpatients receiving high intensity VNS, TWA was reduced from 75.6±5.7 to51.8±2.5 μV at twelve months (†p<0.001). In the ten patients receivinglow intensity VNS, TWA was reduced from 64.0±0.5 to 48.5±2.5 μV attwelve months (*p<0.05). For all of the 25 patients, TWA was reducedfrom 71.0±4.6 to 50.5±1.8 μV at twelve months (‡p<0.0001). Asillustrated in FIG. 16, the change in TWA levels was significant for allpatients.

FIG. 17 is a bar chart 1700 illustrating the heart rate turbulence slope(TS) levels (in msec) taken at baseline, at six months, and at twelvemonths for subjects receiving low intensity stimulation (pulse amplitudeless than 2.0 mA), subjects receiving high intensity stimulation (pulseamplitude greater than or equal to 2.0 mA), and overall for allsubjects. In the fifteen patients receiving high intensity VNS, therewas a significant increase in TS at six months (from 4.4±2.5 to 7.0±0.3msec, †p<0.005) with a further increase at twelve months (to 8.9±0.8msec, *p<0.025). In the overall cohort of 25 patients, there wereincreases in TS at six months (from 4.6±0.8 to 7.2±1.2 msec, ‡p<0.001)with a further increase at twelve months (to 7.8±1.3 msec, *p<0.025).Notably, the low intensity subjects did not experience a statisticallysignificant change in their TS levels. This suggests that only highintensity stimulation can produce improvement in TS, and is thereforemore efficacious in treating heart failure patients.

As a result of these experiments, it is believed that chronic, highintensity VNS stimulation for autonomic regulation therapy in patientswith symptomatic heart failure can decrease cardiac electricalinstability, as reflected in reduced TWA levels and suppression of VT,and can improve baroreflex sensitivity, as reflected in increased HRTslope, both indicators of cardiovascular mortality risk. However, thereappears to be an intensity-related effect indicative of a dose-responserelationship of VNS, underscoring the importance of appropriate VNSparameter selection to optimize the potential benefits of ART. Thismethod of chronic VNS may provide a safe and effective means not only toimprove cardiac mechanical function in patients with depressed leftventricular ejection fraction (LVEF) but also to protect againstlife-threatening ventricular arrhythmias and to improve cardioprotectiveautonomic reflexes.

In accordance with embodiments of the present invention, TWA and/or TSmay be utilized when titrating stimulation and determining optimalstimulation parameters. During titration, the stimulation intensity maybe increased until a target TWA magnitude or target TWA change frombaseline is detected. The targets may vary, but some possible target TWAmagnitudes include, for example, 45 μV, 47 μV, or 50 μV, and somepossible target TWA changes from baseline include, for example, 5 μV,7.5 μV, 10 μV, 12.5 μV, or 15 μV. Alternatively, the stimulationintensity may be increased until a target TS magnitudes or target TSchange from baseline is detected. The targets may vary, but somepossible target TS magnitudes include, for example, 1.0 msec, 2.5 msec,or 5.0 msec, and some possible target TS changes from baseline include,for example, increases of 25%, 50%, 75%, 100%, 125%, or 150%.

As described above, the heart rate measurements used to determine TWAand/or TS levels may be made by the implanted device using an implantedECG heart rate sensor. In other embodiments, the heart rate measurementsmay be made using an external heart rate sensor. This sensor may be incommunication with the implanted device or an external device, which cancalculate the TWA and/or TS levels based on the ECG signals obtained bythe external heart rate sensor.

In accordance with various embodiments, the frequency with which thesubject's heart rate is measured and the TWA and/or TS levels aredetermined may vary. In some embodiments, the heart rate is measured andTWA and/or TS levels calculated on a substantially continuous basisduring the titration process and optionally after titration is completedin order to determine whether subsequent intensity changes may bedesired. In other embodiments, the heart rate measurement and TWA and/orTS level calculations may be performed on a periodic basis, such ase.g., daily, weekly, monthly, semi-annually, or annually. This may beperformed only during the initial titration process or also aftertitration has been completed. In some embodiments, multiple measurementscan be made daily or weekly and used to generate a more robust averagedaily or weekly value. In other embodiments, the heart rate measurementsand TWA and/or TS level calculations may be made on demand by thesubject's health care provider. For example, the health care providermay transmit a control input to the implanted device to cause theimplanted device to begin a period of heart rate monitoring and/orTWA/TS calculations.

Other variations of methods of utilizing TWA monitoring to deliverstimulation therapy may be used. In embodiments described herein, theTWA baseline value is established either prior to implantation or in thepost-implant period before initiation of stimulation. In otherembodiments, after delivery of VNS therapy for an extended period oftime, the stimulation may be suspended for some period of time and a newTWA baseline value determined. It may be desirable to reset the TWAbaseline on a periodic basis, such as, e.g., after the patient hasreceived one month, several months, one year, or several years ofautonomic regulation therapy.

In other embodiments, instead of a target TWA change from baseline TWA,the target may be an absolute value of TWA magnitude, rather than arelative change from baseline. For example, if the magnitude of theobserved TWA is above a threshold level (e.g., 65 μV), then the devicewould increase stimulation intensity until the TWA decreases to anacceptable level.

In embodiments described above, the neurostimulation system provides animplantable device providing closed-loop therapy, wherein adjustments tothe stimulation intensity are made based on TWA, TS, and/or TOcalculations from cardiac signals monitored by the implanted device. Inother embodiments, the cardiac signals may be made by a differentimplanted device or an external device in communication with theimplanted stimulator. In yet other embodiments, the neurostimulationsystem could be open loop without making automatic changes to thestimulation intensity. In these embodiments, the cardiac signals may bemade by the implanted device or by an external device, and the TWA, TS,and/or TO calculations based on those cardiac signals may be made by theimplanted device or by an external device. Information about the TWA,TS, and/or TO calculations (e.g., magnitudes, changes from baseline,historical measurements, etc.) could be communicated to the patientand/or health care provider using, for example, an external device. Thepatient and/or health care provider can use this information to makeadjustments to the stimulation therapy, to make adjustments to othertherapies, such as medication adjustments, or merely to monitor thepatient's progress.

In accordance with embodiments of the invention, examples are providedbelow:

Example 1

A method of operating an implantable medical device (IMD) comprising aneurostimulator coupled to an electrode assembly, said neurostimulatoradapted to deliver a stimulation signal to a patient, said methodcomprising: monitoring an electrocardiogram (ECG) of the patient;activating the IMD to deliver to the patient a plurality of stimulationsignals at increasing stimulation intensities until a target thresholdis detected, wherein the target threshold comprises one or more of atarget T-wave alternans (TWA) threshold, a target heart rate turbulenceslope (TS) threshold, and a target heart rate turbulence onset (TO)threshold; and activating the IMD to deliver a therapeutic level ofstimulation corresponding to the stimulation intensity at which thetarget threshold was detected.

Example 2

The method according to Example 1, wherein: the target thresholdcomprises the target TWA threshold.

Example 3

The method according to Example 2, wherein: the target TWA thresholdcomprises a TWA less than a target TWA magnitude.

Example 4

The method according to Example 3, wherein: the target TWA magnitudecomprises approximately 47 μV.

Example 5

The method according to Example 2, further comprising: computationallydetermining a baseline TWA for the patient; wherein the target TWAthreshold comprises a change in TWA from the baseline TWA equal to orgreater than a target TWA change.

Example 6

The method according to Example 5, wherein: the target TWA changecomprises approximately 10 μV.

Example 7

The method according to Example 5, further comprising: performing abaseline update process, the baseline update process comprising:temporarily ceasing the delivery of stimulation to the patient;monitoring the ECG of the patient to determine an updated baseline TWAfor the patient; activating the IMD to deliver to the patient aplurality of stimulation signals at increasing stimulation intensitiesuntil a target change in TWA from the updated baseline TWA is observed;and activating the IMD to deliver a therapeutic level of stimulationcorresponding to the stimulation intensity during which the targetchange in TWA from the updated baseline TWA was observed.

Example 8

A method of operating an implantable medical device (IMD) comprising aneurostimulator coupled to an electrode assembly, said neurostimulatoradapted to deliver a stimulation signal to a patient, said methodcomprising: monitoring an electrocardiogram (ECG) of the patient todetermine a baseline for the patient, wherein the baseline comprises oneor more of a baseline T-wave alternans (TWA), a baseline heart rateturbulence slope (TS), and a baseline heart rate turbulence onset (TO);activating the IMD to deliver to the patient a plurality of stimulationsignals at increasing stimulation intensities until a target change fromthe baseline is observed; and identifying a neural fulcrum zonecorresponding to the stimulation intensity during which the targetchange from the baseline was observed.

Example 9

The method according to Example 8, wherein: the baseline comprises thebaseline TWA; and the target change from the baseline comprises a targetchange in TWA from the baseline TWA.

Example 10

The method according to Example 8, further comprising: activating theIMD to chronically deliver stimulation signals in the identified neuralfulcrum zone.

Example 11

The method according to Example 10, wherein said activating the IMD tochronically deliver stimulation signals in the identified neural fulcrumzone comprises activating the IMD to treat chronic cardiac dysfunction.

Example 12

The method according to Example 8, wherein: said activating the IMD todeliver to the patient the plurality of stimulation signals atincreasing stimulation intensities comprises activating the IMD todeliver to the patient the plurality of stimulation signals atincreasing stimulation output currents until a target change from thebaseline is observed.

Example 13

The method according to Example 8, wherein: said IMD is adapted todeliver the stimulation signal to a vagus nerve of the patient.

Example 14

The method according to Example 8, further comprising: performing abaseline update process, the baseline update process comprising:temporarily ceasing the delivery of stimulation to the patient;monitoring the ECG of the patient to determine an updated baseline forthe patient; activating the IMD to deliver to the patient a plurality ofstimulation signals at increasing stimulation intensities until a targetchange from the updated baseline is observed; and identifying an updatedneural fulcrum zone corresponding to the stimulation intensity duringwhich the target change from the updated baseline was observed.

Example 15

A method of operating an implantable medical device (IMD) comprising aneurostimulator coupled to an electrode assembly, said neurostimulatoradapted to deliver a stimulation signal to a patient, said methodcomprising: computationally determining a cardiac magnitude value forthe patient, wherein the cardiac magnitude value comprises one or moreof a T-wave alternans (TWA) magnitude value, a heart rate turbulenceslope (TS) magnitude value, and a heart rate turbulence onset (TO)magnitude value; activating the IMD to deliver to the patient aplurality of stimulation signals at increasing stimulation intensitiesuntil the determined cardiac magnitude value reaches to a target cardiacmagnitude; and activating the IMD to deliver a therapeutic level ofstimulation corresponding to the stimulation intensity during which thedetermined cardiac magnitude value reached the target cardiac magnitude.

Example 16

The method according to Example 15, wherein: the computationallydetermining the cardiac magnitude value for the patient comprisescomputationally determining the TWA magnitude value; the activating theIMD to deliver to the patient the plurality of stimulation signals atincreasing stimulation intensities comprises activating the IMD todeliver to the patient the plurality of stimulation signals atincreasing stimulation intensities until the determined TWA magnitudevalue reaches to a target TWA magnitude; and the activating the IMD todeliver the therapeutic level of stimulation comprises activating theIMD to deliver the therapeutic level of stimulation corresponding to thestimulation intensity during which the determined TWA magnitude valuereached the target TWA magnitude.

Example 17

The method according to Example 15, wherein: said computationallydetermining the cardiac magnitude value for the patient is performed bythe IMD.

Example 18

A neurostimulation system, comprising: an implantable medical device(IMD) comprising: an electrode assembly; a neurostimulator coupled tothe electrode assembly, wherein the neurostimulator is adapted todeliver a stimulation signal to a patient; and an electrocardiogram(ECG) sensor; and a control system. The control system being programmedto: monitor the ECG of the patient using the ECG sensor; activate theIMD to deliver to the patient a plurality of stimulation signals atincreasing stimulation intensities until a target threshold is detected,wherein the target threshold comprises one or more of a target T-wavealternans (TWA) threshold, a target heart rate turbulence slope (TS)threshold, and a target heart rate turbulence onset (TO) threshold; andactivate the IMD to deliver a therapeutic level of stimulationcorresponding to the stimulation intensity at which the target thresholdwas detected.

Example 19

The system according to Example 18, wherein the target thresholdcomprises the target TWA threshold.

Example 20

The system according to Example 19, wherein the control system isprogrammed to: activate the IMD to deliver to the patient the pluralityof stimulation signals at increasing stimulation intensities until a TWAless than a target TWA magnitude is detected.

Example 21

The system according to Example 20, wherein: the target TWA magnitudecomprises approximately 47 μV.

Example 22

The system according to Example 18, wherein the control system isprogrammed to: computationally determine a baseline for the patient,wherein the baseline comprises one or more of a baseline TWA, a baselineTS, and a baseline TO; and activate the IMD to deliver to the patientthe plurality of stimulation signals at increasing stimulationintensities until a change from the baseline equal to or greater than atarget change is detected.

Example 23

The system according to Example 22, wherein: the baseline comprises thebaseline TWA; the target change comprises a target TWA change ofapproximately 10 μV.

Example 24

The system according to Example 22, wherein the control system isprogrammed to: perform a baseline update process, the baseline updateprocess comprising: temporarily ceasing the delivery of stimulation tothe patient; monitoring the ECG of the patient to determine an updatedbaseline for the patient; activating the IMD to deliver to the patient aplurality of stimulation signals at increasing stimulation intensitiesuntil a target change from the updated baseline is observed; andactivating the IMD to deliver a therapeutic level of stimulationcorresponding to the stimulation intensity during which the targetchange from the updated baseline was observed.

Example 25

A neurostimulation system, comprising: an implantable medical device(IMD) comprising: an electrode assembly; a neurostimulator coupled tothe electrode assembly, wherein the neurostimulator is adapted todeliver a stimulation signal to a patient; and an electrocardiogram(ECG) sensor; and a control system, wherein the control system isprogrammed to perform any of the methods described above in Examples1-17.

Example 26

A neurostimulation system, comprising: an implantable medical device(IMD) comprising: an electrode assembly; a neurostimulator coupled tothe electrode assembly, wherein the neurostimulator is adapted todeliver a stimulation signal to a patient; an electrocardiogram (ECG)sensor; and a control system. The control system being programmed to:activate the IMD to deliver to the patient a plurality of stimulationsignals; monitor the ECG of the patient using the ECG sensor; anddetermine a cardiac value based on the monitored ECG, wherein thecardiac value comprises one or more of a T-wave alternans (TWA) value, aheart rate turbulence slope (TS) value, and a heart rate turbulenceonset (TO) level.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A method of operating an implantable medicaldevice (IMD) comprising a neurostimulator coupled to an electrodeassembly, said neurostimulator adapted to deliver a stimulation signalto a patient, said method comprising: computationally determining acurrent cardiac magnitude value for the patient, wherein the cardiacmagnitude value comprises one or more of a T-wave alternans (TWA)magnitude value, a heart rate turbulence slope (TS) magnitude value, ora heart rate turbulence onset (TO) magnitude value; activating the IMDto deliver to the patient a plurality of stimulation signals atincreasing stimulation intensities until the current cardiac magnitudevalue reaches a target cardiac magnitude; and activating the IMD todeliver a therapeutic level of stimulation corresponding to thestimulation intensity in response to which the current cardiac magnitudevalue reached the target cardiac magnitude.
 2. The method of claim 1,wherein: computationally determining the current cardiac magnitude valuefor the patient comprises computationally determining the TWA magnitudevalue; activating the IMD to deliver to the patient the plurality ofstimulation signals at increasing stimulation intensities comprisesactivating the IMD to deliver to the patient the plurality ofstimulation signals at increasing stimulation intensities until thecurrent TWA magnitude value reaches a target TWA magnitude; andactivating the IMD to deliver the therapeutic level of stimulationcomprises activating the IMD to deliver the therapeutic level ofstimulation corresponding to the stimulation intensity during which thecurrent TWA magnitude value reached the target TWA magnitude.
 3. Themethod of claim 1, wherein computationally determining the cardiacmagnitude value for the patient is performed by the IMD.
 4. The methodof claim 1, wherein the target cardiac magnitude is a target TWAmagnitude comprising approximately 47 μV.
 5. The method of claim 1,further comprising determining a baseline cardiac magnitude value forthe patient; wherein the target cardiac magnitude comprises a targetchange in the current cardiac magnitude from the baseline cardiacmagnitude.
 6. The method of claim 5, wherein the target change is atarget TWA change comprising approximately 10 μV.
 7. The method of claim5, further comprising identifying a neural fulcrum zone corresponding tothe stimulation intensity in response to which the target change fromthe baseline was observed.
 8. The method of claim 5, further comprisingperforming a baseline update process, the baseline update processcomprising: temporarily ceasing the delivery of the stimulation to thepatient; monitoring an ECG of the patient to determine an updatedbaseline for the patient; activating the IMD to deliver to the patient aplurality of stimulation signals at increasing stimulation intensitiesuntil the target change from the updated baseline is observed; andactivating the IMD to deliver a therapeutic level of stimulationcorresponding to the stimulation intensity in response to which thetarget change from the updated baseline was observed.
 9. Aneurostimulation system, comprising: an implantable medical device (IMD)comprising: an electrode assembly; a neurostimulator coupled to theelectrode assembly, wherein the neurostimulator is adapted to deliver astimulation signal to a patient; and a control system programmed to:computationally determine a current cardiac magnitude value for thepatient, wherein the cardiac magnitude value comprises one or more of aT-wave alternans (TWA) magnitude value, a heart rate turbulence slope(TS) magnitude value, or a heart rate turbulence onset (TO) magnitudevalue; activate the IMD to deliver to the patient a plurality ofstimulation signals at increasing stimulation intensities until thecurrent cardiac magnitude value reaches a target cardiac magnitude; andactivate the IMD to deliver a therapeutic level of stimulationcorresponding to the stimulation intensity in response to which thecurrent cardiac magnitude value reached the target cardiac magnitude.10. The neurostimulation system of claim 9, wherein the control systemis programmed to: computationally determine the current cardiacmagnitude value for the patient by computationally determining the TWAmagnitude value; activate the IMD to deliver to the patient theplurality of stimulation signals at increasing stimulation intensitiesby activating the IMD to deliver to the patient the plurality ofstimulation signals at increasing stimulation intensities until thecurrent TWA magnitude value reaches a target TWA magnitude; and activatethe IMD to deliver the therapeutic level of stimulation by activatingthe IMD to deliver the therapeutic level of stimulation corresponding tothe stimulation intensity in response to which the current TWA magnitudevalue reached the target TWA magnitude.
 11. The neurostimulation systemof claim 9, wherein the target cardiac magnitude is a target TWAmagnitude comprising approximately 47 μV.
 12. The neurostimulationsystem of claim 9, wherein the control system is further programmed todetermine a baseline cardiac magnitude value for the patient; whereinthe target cardiac magnitude comprises a target change in the currentcardiac magnitude from the baseline cardiac magnitude.
 13. Theneurostimulation system of claim 12, wherein the target change is atarget TWA change comprising approximately 10 μV.
 14. Theneurostimulation system of claim 12, wherein the control system isfurther programmed to identify a neural fulcrum zone corresponding tothe stimulation intensity in response to which the target change fromthe baseline was observed.
 15. The neurostimulation system of claim 12,wherein the control system is further programmed to perform a baselineupdate process, the baseline update process comprising: temporarilyceasing the delivery of the stimulation to the patient; monitoring anECG of the patient to determine an updated baseline for the patient;activating the IMD to deliver to the patient a plurality of stimulationsignals at increasing stimulation intensities until the target changefrom the updated baseline is observed; and activating the IMD to delivera therapeutic level of stimulation corresponding to the stimulationintensity in response to which the target change from the updatedbaseline was observed.
 16. A neurostimulation system, comprising: animplantable medical device (IMD) comprising: an electrode assembly; aneurostimulator coupled to the electrode assembly, wherein theneurostimulator is adapted to deliver a stimulation signal to a patient;an electrodcardiogram (ECG) sensor; and a control system programmed to:activate the IMD to deliver to the patient a plurality of stimulationsignals; monitor the ECG of the patient using the ECG sensor; anddetermine a cardiac value based on the monitored ECG, wherein thecardiac value comprises one or more of a T-wave alternans (TWA) value, aheart rate turbulence slope (TS) value, or a heart rate turbulence onset(TO) level.
 17. The neurostimulation system of claim 16, wherein thecontrol system is further programmed to determine a cardiac valuebaseline for the patient.
 18. The neurostimulation system of claim 17,wherein the control system is further programmed to determine whether atarget change from the cardiac value baseline has occurred in responseto the delivery of the plurality of stimulation signals.
 19. Theneurostimulation system of claim 18, wherein the control system isfurther programmed to, in response to determining that the target changehas occurred, activate the IMD to deliver to the patient therapeuticstimulation at a level causing the target change from the cardiac valuebaseline.
 20. The neurostimulation system of claim 18, wherein thecontrol system is further programmed to, in response to determining thatthe target change has occurred, identify a neural fulcrum zonecorresponding to a stimulation intensity causing the target change fromthe cardiac value baseline.